Composition and method of the use of colchicine oral liquid

ABSTRACT

Oral liquid colchicine formulations are described herein. Methods of using the oral liquid colchicine formulations are also provided.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/358,621, filed on Nov. 22, 2016, entitled “COMPOSITION AND METHOD OFUSE OF COLCHICINE ORAL LIQUID” which claims the benefit under 35 U.S.C.§ 119 of U.S. provisional application 62/306,232, filed Mar. 10, 2016,the entire contents of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Colchicine is an alkaloid compound found in plant extracts that is usedto treat gout, familial Mediterranean fever (FMF), pericarditis,Behçet's disease, and atrial fibrillation. Colchicine has also been usedto treat amyloidosis, calcium pyrophosphate deposition disease(pseudogout), cirrhosis of the liver, sarcoid arthritis, andinflammatory diseases. Colchicine is administered to patients as a solidoral dosage form, such as a tablet or capsule. A standard dosage ofcolchicine is typically administered to patients once or twice a day.

Colchicine has previously been shown to be unstable at room temperaturein solution. An article published in Drug Development and IndustrialPharmacy, 15(11), 1905-1909 (1989) by Habib, et. al., investigated thestability of colchicine and showed that there is photodegradation ofcolchicine in solution, especially in the presence of glycerin. Otheradditives, such as lithium carbonate, p-aminobenzoic acid, and uricacid, used in this study did not prevent the degradation of thecolchicine, and furthermore, are not acceptable excipients for an oralsolution.

SUMMARY OF THE INVENTION

The invention in some aspects is a method of treating a colchicinesensitive disorder, by orally administering a composition, comprising anoral liquid colchicine formulation to a human subject having acolchicine sensitive disorder in an effective amount to treat thedisorder. The colchicine sensitive disorder in some embodiments isselected from gout, familial Mediterranean fever (FMF), pericarditis,Behçet's disease, atrial fibrillation, amyloidosis, calciumpyrophosphate deposition disease (pseudogout), cirrhosis of the liver,sarcoid arthritis, inflammatory diseases, and Disk diseases & relatedspinal disorders. In some embodiments the oral liquid colchicineformulation is any of the oral liquid colchicine formulations describedherein.

The invention in other aspects is a pharmaceutical solution orsuspension suitable for oral administration comprising colchicine and apharmaceutically acceptable solvent system comprised of one or moreagents selected from the group consisting of water, glycols, bufferingagents, sweeteners, flavoring agents, preservatives and dyes. Thebuffering agent in some embodiments is about 0.12% (w/v) citric acid(anhydrous). In some embodiments the sweetener is about 0.2% (w/v)sucralose. In other embodiments the flavoring agent is about 0.125%(w/v) artificial grape flavor and/or Flavor Cherry 825.662. In someembodiments the preservative is about 0.3% (w/v) of benzyl alcohol. Insome embodiments the preservative is about 0.2% (w/v) of citric acid,anhydrous. In other embodiments the dye comprises one or more of D&CYellow No. 10 and FD&C Red No. 40. In some embodiments the dye comprisesabout 0.01% (w/v) FD&C Red No. 40. In some embodiments the thickeningagent comprises about 0.15% (w/v) xanthan gum. The concentration ofcolchicine in the solution in other embodiments is 0.01-1.0 mg/ml or0.2-0.60 mg/ml.

In other embodiments the pharmaceutically acceptable solvent system iscomprised of one or more agents selected from the group consisting ofwater, propylene glycol, glycerin, benzyl alcohol, parabens, citricacid, xanthan gum, sucralose, a dye, and a flavoring agent and/or tasteenhancing agent.

In yet other embodiments the pharmaceutically acceptable solvent systemis comprised of the following components:

Ingredient % w/v Benzyl Alcohol 0.3 Citric Acid, Anhydrous 0.2Colchicine* 0.012 FD&C Red No. 40 0.01 Dibasic Sodium Phosphate,Heptahydrate 1.2 Flavor Cherry 825.662 0.125 Propylene Glycol 5 Glycerin5 Sucralose 0.15 Xanthan Gum 0.15 Water Q.S. *calculated on theanhydrous, solvent free basis

In some embodiments the oral liquid formulations described herein arenon-sterile.

In some embodiments the oral liquid formulations comprises compatibleand stable preservative. In other embodiments the compatible and stablepreservative is benzyl alcohol.

In some embodiments the colchicine formulation has a viscosity in therange of 40-800 cps. In other embodiments the colchicine formulation hasa viscosity of 80-250 cps.

In other embodiments the colchicine formulation is volume packaged 60mL-473 mL, and more preferably 150 ml-300 mL.

The colchicine formulations of the invention may be provided in any typeof bottle acceptable for oral liquid medications. In some embodimentsthe colchicine formulation is packaged in a plastic bottle, such as HDPE(high density polyethylene bottles) or PET. The colchicine solution mayalso be packaged in glass bottles, which could be amber or clear, inother embodiments. The caps of the bottles may or may not have aninduction seal and could be easy to open or tamper resistant. Thebottles and/or the packaging could be multi use or single dose units. Apreferred embodiment is a 190 ml HDPE container closure system with acap with an induction seal.

In some embodiments the oral liquid colchicine formulation is stable atroom temperature for at least 3 months, at least 6 months, at least 18months, or at least 24 months. In some embodiments the oral liquidcolchicine formulation is stable at accelerated temperatures for atleast 1 month, at least 2 months, at least 3 months, or at least 6months. In some embodiments the oral liquid colchicine formulation isdetermined to be stable when the solution has less than 5%, less than4%, less than 3%, less than 2%, less than 1% or less than 0.5% of anyone degradant. In other embodiments the oral liquid colchicineformulation is determined to be stable when the solution has less than5%, less than 4%, less than 3%, less than 2%, less than 1% or less than0.5% of total degradants. In some embodiments, degradants include βlumicolchicine, γ-lumicolchicine, colchiceine, and any other individualunknown impurities.

Each of the limitations of the invention can encompass variousembodiments of the invention. It is, therefore, anticipated that each ofthe limitations of the invention involving any one element orcombinations of elements can be included in each aspect of theinvention. This invention is not limited in its application to thedetails of construction and the arrangement of components set forth inthe following description or illustrated in the drawings. The inventionis capable of other embodiments and of being practiced or of beingcarried out in various ways. Also, the phraseology and terminology usedherein is for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing”, “involving”, and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

BRIEF DESCRIPTION OF DRAWINGS

The figures are illustrative only and are not required for enablement ofthe invention disclosed herein.

FIG. 1 depicts a chromatograph. Sample, colchicine standard, and diluentblank can be found from top to bottom.

FIG. 2 depicts a chromatograph of an exemplary liquid oral colchicinesolution. Diluent blank, placebo, red color, benzyl alcohol, flavorcherry, and colchicine standard are shown from top to bottom.

FIG. 3 shows the calibration curve of colchicine in Caco-2 transportbuffer.

FIG. 4 shows a chromatogram of colchicine in Caco-2 buffer.

FIGS. 5A-5F show representative colchicine chromatograms. FIGS. 5A-5Bshow chromatograms of liquid colchicine dosing (FIG. 5A) and liquid A→Breceiver sample (FIG. 5B). FIGS. 5C-5D show chromatograms of colchicineUSP tablet dosing (FIG. 5C) and liquid A→B receiver sample (FIG. 5D).FIGS. 5E-5F show chromatograms of colchicine capsule dosing (FIG. 5E)and liquid A→B receiver sample (FIG. 5F).

DETAILED DESCRIPTION

Colchicine is administered to patients as a solid oral dosage form, suchas a tablet or capsule. Colchicine has previously been shown to beunstable at room temperature in solution. Habib et al. showed rapidphotodegradation of colchicine in solution, especially in the presenceof glycerin. Other additives, such as lithium carbonate, p-aminobenzoicacid, and uric acid, were used in this study, but did not prevent thedegradation of the colchicine, and furthermore, are not acceptableexcipients for an oral solution. Surprisingly, it was found according tothe invention, that liquid suspensions or solutions of colchicineformulated as an oral solution are stable at ambient temperature andhave stable pH for extended periods of time. For instance the liquidsolutions or suspensions described herein are stable for at least threemonths in refrigerated, ambient, and accelerated temperatures. Thefindings of the invention have important clinical implications. An oralsolution or suspension of colchicine is advantageous for colchicinedosing and administration.

Colchicine,(−)-N-[(7S,12aS)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]-acetamide,is a pale yellow powder soluble in water in 1:25 dilution. Colchicine isan alkaloid found in extracts of certain plants such as Colchicumautumnale and Gloriosa superba. Colchicine arrests cell division inanimals and plants. It has adversely affected spermatogenesis in humansand in some animal species under certain conditions.

The invention encompasses liquid formulations of colchicine. The presentinvention provides for liquid formulation of colchicine, suitable fororal administration that is stable at room temperature. The liquidformulation can be either a solution or a suspension. Colchicine solidoral dosage forms, such as tablets and capsules have been used for theprophylactic treatment of gout and to treat patients suffering from goutflares. In addition to treating patients with gout, colchicine is alsoused to treat patients with Familial Mediterranean Fever (FMF). Studieshave also shown that colchicine may be used to treat patients withcardiovascular disease and various other conditions.

Currently colchicine is primarily used to treat patients suffering fromgout. An oral liquid formulation can provide physicians more flexibilityin designing dosage regimens for their patients. This is particularlyimportant since colchicine is toxic and has a narrow therapeutic index.The methods described herein are useful for the treatment of gout. Thetreatment of gout involves the prophylactic treatment of gout as well asthe treatment of gout flares. The prophylactic treatment of gout refersto the treatment of a patient who has had one or more gout flares, inorder to reduce the occurrence of future gout flares.

Some of the challenges in formulating an oral liquid of colchicineinclude maintaining stability of the colchicine, maintaining an optimumpH, and masking the bitter taste. It is also important to establish aneffective preservative system to prevent the growth of bacteria, mold,and other contaminants. Additionally, the oral liquid colchicine must bepatient friendly and requires suitable packaging, such as a containerclosure system that factors in the potential effects of light and airexposure.

Also provided herein are methods of treating gout, familialMediterranean fever (FMF), Behçet's disease, cardiovascular disease(atrial fibrillation, pericarditis), amyloidosis, calcium pyrophosphatedeposition disease (pseudogout), cirrhosis of the liver, sarcoidarthritis, inflammatory diseases, and Disk diseases & related spinaldisorders comprising administering to a patient, such as a child or anelderly patient, an oral liquid formulation compounded from colchicineas described herein. In some embodiments, oral liquid formulationsdisclosed herein can also be used to treat for other conditions (e.g.,skin conditions) known in the art (Ben-Chetrit E, Levy M. Colchicine:1998 update. Semin Arthritis Rheum. 1998; Yurdakul S, Mat C, Tüzün Y,Ozyazgan Y, Hamuryudan V, Uysal O, Senocak M, Yazici H. A double-blindtrial of colchicine in Behçet's syndrome. Arthritis Rheum. 2001November; 44(11):2686-92. August; 28(1):48-59; Molad Y. Update oncolchicine and its mechanism of action. Curr Rheumatol Rep. 2002 June;4(3):252-6).

Commonly, geriatric populations encounter difficulty being administeredsolid oral dosage forms such as tablets and capsules. This may lead tonon-compliance with the recommended pharmacotherapy with the solid oraldosage forms and likely results in rendering the therapy ineffective.Solid oral dosage forms are usually not favorable for geriatricpopulations due to the potential risk of choking. Additionally, certainsolid oral dosage forms of medications cannot be administered simply bycrushing (e.g., patients requiring various types of feeding tubes)because of the coating or drug delivery mechanism by which the drug isreleased.

As used herein, “colchicine” refers to colchicine base, its salt, orsolvate or derivative or isomer or polymorph thereof. Suitable compoundsinclude the free base, the organic or inorganic salts, isomers, isomersalts, solvates, polymorphs, complexes, etc.

In some embodiments the oral liquid colchicine formulation is stable atroom temperature for at least 3 months, at least 6 months, at least 18months, or at least 24 months. In some embodiments the oral liquidcolchicine formulation is stable at accelerated temperatures for atleast 1 month, at least 2 months, at least 3 months, or at least 6months. In some embodiments the oral liquid colchicine formulation isdetermined to be stable when the solution has less than 5%, less than4%, less than 3%, less than 2%, less than 1% or less than 0.5% of anyone degradant. In other embodiments the oral liquid colchicineformulation is determined to be stable when the solution has less than5%, less than 4%, less than 3%, less than 2%, less than 1% or less than0.5% of total degradants. In some embodiments, degradants include βlumicolchicine, γ-lumicolchicine, colchiceine, and any other individualunknown impurities.

Gout

Gout (or gouty arthritis) is a disease caused by a build-up of uric aciddue to an overproduction of uric acid or a reduced ability of the kidneyto get rid of uric acid. It is more common in males, postmenopausalwomen, and people with high blood pressure. Heavy alcohol use, diabetes,obesity, sickle cell anemia, and kidney disease also increase the risk.The condition may also develop in people who take drugs that interferewith uric acid excretion.

In gout, monosodium urate or uric acid crystals are deposited on thearticular cartilage of joints, tendons and surrounding tissues due toelevated concentrations of uric acid in the blood stream. This provokesan inflammatory reaction of these tissues. Gout is characterized byexcruciating, sudden, unexpected, burning pain, as well as swelling,redness, warmness, and stiffness in the affected joint. Low-grade fevermay also be present. The patient usually suffers from two sources ofpain. The crystals inside the joint cause intense pain whenever theaffected area is moved. The inflammation of the tissues around the jointalso causes the skin to be swollen, tender and sore if it is evenslightly touched. Acute gouty arthritis (alternatively referred to as agout flare or a gout attack) is a sudden attack of pain in affectedjoints, especially in the feet and legs. Chronic gout involves repeatedattacks of joint pain.

In acute gouty arthritis, symptoms develop suddenly and usually involveonly one or a few joints. The big toe, knee, or ankle joints are mostoften affected. The pain frequently starts during the night and is oftendescribed as throbbing, crushing, or excruciating. The joint appearsinfected with signs of warmth, redness, and tenderness. The attacks ofpainful joints may go away in several days, but may return from time totime. Subsequent attacks usually last longer. Some people may progressto chronic gout (chronic gouty arthritis), while others may have nofurther attacks.

If several attacks of gout occur each year, it can lead to jointdeformity and limited motion in joints. Uric acid deposits, calledtophi, develop in cartilage tissue, tendons, and soft tissues. Thesetophi usually develop only after a patient has suffered from the diseasefor many years. Deposits also can occur in the kidneys, leading tochronic kidney failure.

Colchicine can be used for treating adults with acute gouty arthritisand pain in attacks of acute gouty arthritis, and also can be usedbeneficially for treating adults with chronic gout for prophylaxis ofacute gout flares. Although its exact mode of action in the relief ofgout is not completely understood, colchicine is known to decrease theinflammatory response to urate crystal deposition by inhibitingmigration of leukocytes, to interfere with urate deposition bydecreasing lactic acid production by leukocytes, to interfere with kininformation and to diminish phagocytosis and the subsequentanti-inflammatory response. The anti-inflammatory effect of colchicineis relatively selective for acute gouty arthritis. However, other typesof arthritis occasionally respond. It is neither an analgesic nor auricosuric and will not prevent progression to chronic gouty arthritis.It does have a prophylactic, suppressive effect that helps to reduce theincidence of acute attacks and to relieve the residual pain and milddiscomfort that patients with gout occasionally experienced. In someinstances, non-steroidal anti-inflammatory drugs (NSAIDs) may also beprescribed to relieve pain and inflammation in acute gouty arthritisattacks. Strong painkillers, such as codeine, or corticosteroids mayalso be prescribed to relieve the pain.

Colchicine is rapidly absorbed from the gastrointestinal tract. Peakconcentrations occur in 0.5 to 2 hours. The drug and its metabolites aredistributed in leukocytes, kidneys, liver, spleen and the intestinaltract. Colchicine is metabolized in the liver and excreted primarily inthe feces with 10 to 20% eliminated unchanged in the urine. In someembodiments, oral liquid formulations disclosed herein are used to treatgout.

Familial Mediterranean Fever (FMF)

Familial Mediterranean Fever (FMF) is a recessively inherited disordercharacterized by dramatic episodes of fever, serosal inflammation andabdominal pain. This inflammatory disorder is episodic, withself-limited bouts of fever accompanied by unexplained arthritis,sterile peritonitis, pleurisy and/or skin rash. Patients often developprogressive systemic amyloidosis from the deposition of the acute phasereactant serum amyloid A (SAA). In some patients, progressive systemicamyloidosis can lead to kidney failure and death. The factors whichincite an episode are unclear. In some embodiments, colchicine can beprescribed as an anti-inflammatory therapy.

FMF is observed primarily in individuals of non-Ashkenazi Jewish,Armenian, Arab and Turkish background. Although rare in the UnitedStates, incidence of FMF in Middle Eastern populations can be as high as1:7 in Armenian populations and 1:5 in non-Ashkenazi Jewish populations.

FMF attacks are characterized by a massive influx of polymorphonuclearleukocytes (PMNs) into the affected anatomic compartment. At thebiochemical level, patients have been reported to have abnormal levelsof C5a inhibitor (Matzner and Brzezinski, “C5a-inhibitor deficiency inperitoneal fluids from patients with familial Mediterranean fever,” N.Engl. J. Med., 311:287-290 (1984)), neutrophil-stimulatory dihydroxyfatty acids (Aisen et al, “Circulating hydroxy fatty acids in familialMediterranean fever,” Proc. Natl. Acad. Sci. USA, 2:1232-1236 (1985)),and dopamine O-hydroxylase (Barakat et al, “Plasma dopaminebeta-hyroxylase: rapid diagnostic test for recurrent hereditarypolyserositis,” Lancet, 2:1280-1283 (1988)). Although linkage studieshave placed the gene causing FMF (designated MEFV) on chromosome 16p(Pras et al., “Mapping of a gene causing familial Mediterranean fever tothe short arm of chromosome 16,” N. Engl. J. Med., 326:1509-1513 (1992);Shohat et al., “The gene for familial Mediterranean fever in bothArmenians and non-Ashkenazi Jews is linked to the α-globin complex on16p: evidence for locus homogeneity,” Am. J. Hum. Genet., 51:1349-1354(1992); Pras et al, “The gene causing familial Mediterranean fever mapsto the short arm of chromosome 16 in Druze and Moslem Arab families,”Hum. Genet., 94:576-577(1994); French FMF Consortium, “Localization ofthe familial Mediterranean fever gene (FMF) to a 250 kb-interval innon-Ashkenazi Jewish founder haplotypes,” Am. J. Hum. Genet.,59:603-612(1996)), the genetic basis of FMF has not previously beenidentified. In some embodiments, oral liquid formulations disclosedherein are used to treat FMF.

Behçet's Disease

Behçet's disease is a chronic multisystem disease characterized by oraland genital aphthae, arthritis, cutaneous lesions, and ocular,gastrointestinal, and neurologic manifestations. It was first describedby the Turkish dermatologist Hulusi Behcet in 1937 as “recurrent oralaphthous ulcers, genital ulcers, and ‘hypopyon-uveitis.’” The diagnosisof Behcet's disease is based on clinical criteria as established byO'Duffy and Goldstein and the International Study Group. Complexaphthosis is the presence of almost constant, multiple oral or oral andgenital aphthae in the absence of systemic manifestations. Thesepatients must be distinguished from those with Behcet's disease.Colchicine has been used as a treatment for Behcet's disease through itsability to inhibit of neutrophil functions (Hirohata et al., Behcet'sdisease. Arthritis Res Ther 2003 5:139 DOI: 10.1186/ar757). In someembodiments, oral liquid formulations disclosed herein are used to treatBehcet's Disease.

The prevalence of Behcet's disease is higher in the Middle East andJapan where it is approximately 1 in 1000. The disease is far lesscommon in northern Europe, the United States, and the United Kingdom.The mean age of onset ranges from the mid to late 20s to the fourthdecade, according to several series, with a slightly higher male tofemale ratio. It is relatively rare in children and the elderly.Behcet's disease is also uncommon among black Africans who, when theyare affected, tend to have more mucocutaneous features. Although adefinitive pattern of inheritance has not been elucidated, familialcases have been reported. Patients with complex aphthosis are probably asubset of patients with recurrent aphthous stomatitis, which is definedas the recurrence of 1 or more painful oral ulcers at intervals rangingfrom days to months. The prevalence of recurrent aphthosis ranges from5% to 66%. Onset may occur in childhood or adolescence and some patientsexperience a decrease in frequency with advancing age. (source: J. VGhate and J. L. Jorizzo, “Behçet's disease and complex aphthosis”,Journal of the American Academy of Dermatology, 1999, 40(1), 1-18.)

Cardiovascular Disease (Atrial Fibrillation, Pericarditis)

Cardiovascular disease (CVD) involves the heart of blood vessels. CVDincludes, but is not limited to coronary artery diseases (CAD), stroke,hypertensive heart disease, rheumatic heart disease, cardiomyopathy,atrial fibrillation, congenital heart disease, endocarditis,pericarditis, aortic aneurysms, peripheral artery disease, and venousthrombosis.

One very typical and dangerous arrhythmia is atrial fibrillation (AFIB).AFIB is the most common cardiac arrhythmia resulting in hospitalizationin the United States. AFIB is identified by irregular heart rhythms andis clinically defined as uncoordinated contractions of the atria.Patients often experience palpitations and have an increased risk ofstroke. Some patients may be asymptomatic. Approximately one-third ofall strokes are due to AFIB. Furthermore, the presence of AFIB makesstrokes 5-times more likely and 2-times more debilitating.

The role of colchicine in inflammation, microtubule disruption, adhesionof neutrophils, and other qualities, makes it a promising treatment forsome cardiovascular diseases (Deftereos et al., Colchicine and theHeart: pushing the envelope. J Am Coll Cardiol. 2013; 62(20):1817-1825.doi:10.1016/j.jacc.2013.08.726; Tong et al., Colchicine incardiovascular disease: an ancient drug with modern tricks. 2016 Heartdoi:10.1136/heartjnl-2015-309211). In some embodiments, oral liquidformulations disclosed herein are used to treat cardiovascular diseases(e.g., atrial fibrillation and pericarditis).

Amyloidosis

Amyloidosis is a rare and potentially fatal disease that can be eitherlocalized or systemic. There are four major types of amyloidosis. Thefour major types include immunoglobulin (primary) amyloidosis, reactive(secondary) amyloidosis, beta-2 microglobulin amyloidosis and hereditaryamyloidosis. Each different type of amyloidosis presents a differentprognosis and stems from different underlining conditions. Thepathologic features of amyloid deposits include beta-pleated sheetstructures that are composed of amyloid fibrils with diameters between 8to 10 nm. B eta-pleated sheets can be viewed under polarized light afterbeing stained using Congo Red stain, these stained fibrils display anapple green birefringence.

Secondary amyloidosis is associated with chronic inflammatory diseasessuch as FMF. The precursor protein responsible for constructing theamyloid fibrils associated with secondary amyloidosis is serum amyloidA, an acute-phase reactant. Typical sites of amyloid accumulationinclude the spleen, liver, lymph nodes, adrenal glands, and the kidneys.Symptoms that are nonspecific include complaints of weakness andfatigue. Specific complaints are directly associated to organinvolvement, these symptoms commonly include edema and pain. In someembodiments, oral liquid formulations disclosed herein are used to treatamyloidosis.

Calcium Pyrophosphate Deposition Disease (Pseudogout)

Calcium pyrophosphate deposition disease (CPDD), also known aspseudogout, chondrocalcinosis, and pyrophosphate arthropathy, is arheumatologic disorder with varied symptoms and signs arising from theaccumulation of crystals of calcium pyrophosphate dihydrate in theconnective tissues.

Pseudogout refers to the acute symptoms of joint inflammation orsynovitis: red, tender, and swollen joints that may resemble goutyarthritis. The disorder is more common in older adults. It may beasymptomatic, or it can be associated with osteoarthritis, or it canpresent as an acute or chronic inflammatory arthritis that causes painin one or more joints. The white blood cell count is often raised.

The arthritis is usually polyarticular (inflammation of several jointsin the body), although it may begin as monoarticular (one joint). CPPDcrystals tend to form within articular tissues. Knees are the mostcommonly affected joints, along with wrists and hips. In rare cases,pseudogout may affect the spinal canal and cause damage to the spinalcord. In some embodiments, oral liquid formulations disclosed herein areused to treat pseudogout.

Cirrhosis of the Liver

Cirrhosis, a condition in which the liver does not function properly dueto long-term damage, typically comes on slowly over months or years.Early on, there are often no symptoms. As the disease worsens, a subjectmay become tired, weak, itchy, have swelling in the lower legs, developyellow skin, bruise easily, have fluid build-up in the abdomen, ordevelop spider-like blood vessels on the skin. The fluid build-up in theabdomen may become spontaneously infected. Other complications includehepatic encephalopathy, bleeding from dilated veins in the esophagus ordilated stomach veins, and liver cancer. Hepatic encephalopathy resultsin confusion and possibly unconsciousness. Colchicine has been shown tohave anti-fibrotic effects in relation to hepatic diseases (Leung etal., Colchicine—Update on mechanisms of action and therapeutic uses.2015. Seminar in Arthritis and Rheumatism. 45 (3), 257-67).

Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C,and non-alcoholic fatty liver disease. Typically, more than two or threedrinks per day over a number of years is required for alcoholiccirrhosis to occur. Non-alcoholic fatty liver disease is due to a numberof reasons, including being overweight, diabetes, high blood fats, andhigh blood pressure. A number of less common causes include autoimmunehepatitis, primary biliary cirrhosis, hemochromatosis, certainmedications, and gallstones. Cirrhosis is characterized by thereplacement of normal liver tissue by scar tissue. These changes lead toloss of liver function. Diagnosis is based on blood testing, medicalimaging, and liver biopsy. In some embodiments, oral liquid formulationsdisclosed herein are used to treat hepatic diseases (e.g., cirrhosis ofthe liver).

Sarcoid Arthritis

Sarcoidosis, a disease involving abnormal collections of inflammatorycells, can be involved with the joints, bones and muscles. This causes awide variety of musculoskeletal complaints that act through differentmechanisms. Approximately 5-15% of cases affect the bones, joints, ormuscles.

Sarcoid arthritis has two classifications: acute or chronic. Sarcoidosispatients with acute arthritis often also accompanies bilateral Hilarlymphadenopathy and Erythema nodosum. Usually true arthritis is notpresent, but instead periarthritis presents itself as a swelling in thesoft tissue around the joints that can be seen by ultrasonographicmethods. These joint symptoms tend to precede or occur at the same timeas erythema nodosum develops. Enthesitis also occurs in about one-thirdof patients with acute sarcoid arthritis, mainly affecting the Achillestendon and heels. Soft tissue swelling at the ankles can be prominent,and biopsy of this soft tissue reveals no granulomas, but does showpanniculitis that is similar to erythema nodosum.

Chronic sarcoid arthritis usually occurs in the setting of more diffuseorgan involvement. The ankles, knees, wrists, elbows, and hands may allbe affected in the chronic form and often in a polyarticular pattern.Dactylitis similar to that seen in Psoriatic arthritis, that isassociated with pain, swelling, overlying skin erythema, and underlyingbony changes may also occur. In some embodiments, oral liquidformulations disclosed herein are used to treat sarcoid arthritis.

Disk Diseases & Related Spinal Disorders

Disk diseases & related spinal disorders are a group of disorders thatare quite painful. It is believed that colchicine acts directly ondiskal inflammation to reduce inflammation in the area surrounding thespinal nerve roots. Colchicine has also been shown to cause an increaseof endorphin-producing neurons in the spinal cord and to preventdeposition of amyloid in damaged disk. In some embodiments the subjecthas diskal back pain and or sciatica. In some embodiments, oral liquidformulations disclosed herein are used to treat disk diseases andrelated spinal disorders.

Formulations

The liquid formulations described herein may include additionalingredients. For instance these additional components may include, butare not limited to, buffering agents, preservatives, sweeteners,flavoring agents, glycols such as propylene glycol and glycerin, asexamples, and coloring agents. Additional excipients such as tonicityagents and chelating agents are within the scope of the embodiments.

Buffering agents maintain the pH when colchicine is compounded into aliquid form. Non-limiting examples of buffering agents include, but arenot limited to, sodium bicarbonate, potassium bicarbonate, magnesiumhydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide,aluminum hydroxide/sodium bicarbonate precipitate, a mixture of an aminoacid and a buffer, a mixture of aluminum glycinate and a buffer, amixture of acid salt and an amino acid and a buffer, and a mixture of analkali salt of an amino acid and a buffer. Additional buffering agentsinclude citric acid, sodium citrate, sodium tartarate, sodium acetate,sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodiumpyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate,dibasic sodium phosphate, trisodium phosphate, tripotassium phosphate,sodium acetate, potassium metaphosphate, magnesium oxide, magnesiumcarbonate, magnesium silicate, calcium acetate, calciumglycerophosphate, calcium chloride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, and other calcium salts. Somebuffering agents also impart effervescent qualities when a powder iscompounded into a liquid. In some embodiments, the colchicine describedherein, when compounded into a liquid form, comprises a buffering agent.

Preservatives include anti-microbials, anti-oxidants, and agents thatenhance sterility. Exemplary preservatives include ascorbic acid,ascorbyl palmitate, benzyl alcohol, BHA, BHT, citric acid, erythorbicacid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodiumbenzoate, sodium bisulfate, sodium metabisulfite, sodium sulfite,parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, andvanillin. In some embodiments, the colchicine described herein, whencompounded into a liquid form, comprises a preservative.

Sweeteners or sweetening agents include any compounds that provide asweet taste to make the product more palatable. This includes naturaland synthetic sugars, natural and artificial sweeteners (e.g.,sucralose), natural extracts and any material that initiates a sweetsensation in a subject. In some embodiments, the colchicine describedherein, when compounded into a liquid form, comprises a sweetener. Inother embodiments, sweeteners in liquid form are used to solvate ordissolve the colchicine described herein.

Sugars illustratively include glucose, fructose, sucrose, xylitol,tagatose, maltitol, isomaltulose, lactitol, sorbitol, mannitol,erythritol, trehalose, maltodextrin, polydextrose, and the like. Othersweeteners include glycerin, inulin, maltol, acesulfame and saltsthereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodiumcyclamate, saccharin and salts thereof, e.g., saccharin sodium orsaccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin,and the like. Sweeteners can be used in the form of crude or refinedproducts such as hydrogenated starch hydrosylates, maltitol syrup, highfructose corn syrup, and as branded proprietary blend products.Sweeteners can be used singly or combinations of two or more. Suitableconcentrations of different sweeteners can be selected based onpublished information, manufacturers' data sheets, and by routinetesting. In certain instances, an above-described flavored solutioncomponent is used to solvate or dissolves colchicine described herein.

In another embodiment, the liquid form comprises a flavoring agent orflavorant to enhance the taste or aroma of the solution component usedto solvate or dissolve the colchicine described herein. Suitable naturalor synthetic flavoring agents can be selected from standard referencebooks, such as Remington: The Science and Practice of Pharmacy (2000)and Fenaroli's Handbook of Flavor Ingredients (1994). Non-limitingexamples of suitable natural flavors, some of which can be readilysimulated with synthetic agents or combinations thereof, include almond,anise, apple, apricot, banana, blackberry, blackcurrant, blueberry,caramel, cherry, chocolate, cinnamon, cranberry, grape, lemon, lime,orange, peppermint, pineapple, raspberry, spearmint, strawberry,vanilla, etc. Also useful, particularly where the composition isintended primarily for pediatric use is tutti-frutti or bubble gumflavor, a compounded flavoring agent based on fruit flavors. Presently,preferred flavoring agents include bubble gum, strawberry, cherry,grape, orange, peppermint, and vanilla. In some embodiments, theresultant liquid form from the colchicine described herein comprises aFlavor Cherry 825.662 flavoring agent. Flavoring agents may be usedsingly or in combinations of two or more.

In further embodiments, the resultant liquid form from the colchicinedescribed herein comprises a coloring agent for identity and/oraesthetic purposes. Suitable coloring agents approved by the U.S. Foodand Drug Administration (FDA) include FD&C Red No. 3, FD&C Red No. 20,FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5,D&C Orange No. 5, D&C Yellow No. 10, caramel, ferric oxide and mixturesthereof.

In further embodiments, the resultant liquid form from the colchicinedescribed herein comprises a thickening agent Thickening agents include,but are not limited to xanthan gum.

In some embodiments other flavoring agents, buffering systems, andpreservatives may be used. The solution is formulated to inhibit growthof bacteria, mold, and yeast for storage at room temperature and ambientconditions.

In some embodiments, the liquid formulation is by % w/v can be found inTable 1. In other embodiments, the formulation includes 0.2-0.4% w/v ofbenzyl alcohol, 0.1-0.3% w/v of anhydrous citric acids, 0.005-0.025% w/vof colchicine, 0.005-0.02% w/v of FD&C Red No. 40, 0.8-1.6% w/v ordibasic sodium phosphate, heptahydrate, 0.75-0.15% w/v of flavor cherry825.662, 2-8% w/v of propylene glycol, 2-10% glycerin, 0.1-0.2% w/v ofsucralose, 0.1-0.2% w/v of xanthan gum, and water. In other embodiments,the formulation includes 0.28-3.2 or 0.3% w/v of benzyl alcohol, 0.2%w/v of anhydrous citric acids, 0.012% w/v of colchicine, 0.01% w/v ofFD&C Red No. 40, 1.2% w/v or dibasic sodium phosphate, heptahydrate,0.125% w/v of flavor cherry 825.662, 5% w/v of propylene glycol, 0.15%w/v of sucralose, 0.15% w/v of xanthan gum, and water.

TABLE 1 Exemplary formulation Ingredient % w/v Benzyl Alcohol 0.3 CitricAcid, Anhydrous 0.2 Colchicine* 0.012 FD&C Red No. 40 0.01 DibasicSodium Phosphate, Heptahydrate 1.2 Flavor Cherry 825.662 0.125 PropyleneGlycol 5 Glycerin 5 Sucralose 0.15 Xanthan Gum 0.15 Water Q.S.*Calculated on the anhydrous, solvent free basis

Storage

The colchicine described herein is stable in various storage conditionsincluding refrigerated, ambient, and accelerated conditions. Stable asused herein refers to the ability of an active agent to maintainactivity under standard stability conditions. Standard stabilityconditions include relative humidity conditions along with thetemperatures, 25 degrees C. 60% RH(RT), 30C 65% RH (ICH), and 40C 75% RH(accelerated), for example.

At refrigerated and ambient conditions, the liquid colchicinecomposition described herein in stable for at least 1 month, at least 2months, at least 3 months, at least 6 months, at least 9 months, atleast 12 months, at least 15 months, at least 18 months, and at least 24months. At accelerated conditions, the colchicine solution describedherein is stable for at least 1 month, at least 2 months, at least 3months and at least 6 months. Accelerated conditions includetemperatures that are above ambient levels. In some instances, anaccelerated condition is at about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 55° C., or about 60° C. Ambientconditions include temperature that is at ambient levels. In someinstances, an ambient condition is at about 20° C., about 21° C., about22° C., about 23° C., about 24° C., about 25° C., about 26° C., about27° C., about 28° C., about 29° C., and about 30° C. Refrigeratedconditions include temperature in typical refrigeration units (e.g. 5±3°C.). In some instances, a refrigerated condition is about 2° C., about3° C., about 4° C., about 5° C., about 6° C., about 7° C., or about 8°C.

Liquid vehicles suitable for the colchicine described herein areselected for a particular oral liquid composition (e.g., solution,suspension, etc.) as well as other properties such as clarity,viscosity, compatibility with excipients, chemical inertness,palatability, odor, and color. Exemplary liquid vehicles include water,ethyl alcohol, glycerin, propylene glycol, syrup (e.g., sugar or othersweetener based, e.g., Ora-Sweet® SF sugar-free flavored syrup), juices(e.g., apple, orange, cranberry, cherry, tomato and the like), otherbeverages (e.g., tea, coffee, soft drinks, milk and the like), oils(e.g., olive, soybean, corn, mineral, castor and the like), andcombinations or mixtures thereof. Certain liquid vehicles, e.g., oil andwater, can be combined together to form emulsions. In some embodiments,water is used as a vehicle for a colchicine oral liquid. In otherembodiments, propylene glycol is used as a vehicle for a colchicine oralliquid. For the liquid colchicine described herein, the solutioncomponent is used as the vehicle for a colchicine oral liquid.

The viscosity of the solution is an important component. In someembodiments the solution has a viscosity in the range of 40-800 cps. Inother embodiments the solution has a viscosity of 80-250 cps.

The colchicine oral liquid compositions may be used for the treatment ofdiseases and conditions described herein. In addition, a method fortreating any of the diseases or conditions described herein in a subjectin need of such treatment involves administration of colchicine oralliquid compositions in therapeutically effective amounts to the subject.In some embodiments, the amount of a given colchicine oral liquidcomposition that corresponds to such an amount varies depending onfactors such as the particular colchicine salt or form, diseasecondition and its severity, the identity (age, weight, sex) of thesubject or patient in need of treatment, but can nevertheless bedetermined according to the particular circumstances surrounding thecase, including, e.g., the specific agent being administered, the liquidcomposition type, the condition being treated, and the subject orpatient being treated.

In further embodiments, the daily dosages appropriate for the colchicineoral liquid compositions described herein are from about 0.2 mg-1.5mg/dose/day or in other embodiments 0.5 mg-1.5 mg/dose/day. In oneembodiment, the daily dosage appropriate for the colchicine liquidcompositions is about 0.6-1.2 mg/dose/day.

The treatment of certain diseases or conditions (e.g., gout, FMF,cardiac disease etc.) in a patient or subject with a colchicine oralliquid composition described herein encompass additional therapies andtreatment agents in some embodiments. Such additional therapies andtreatment regimens include another therapy, e.g., antibiotics, for thetreatment of the particular disease in some embodiments.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice of testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue. The use of the term “or” in the claims is used to mean “and/or”unless explicitly indicated to refer to alternatives only or thealternatives are mutually exclusive, although the disclosure supports adefinition that refers to only alternatives and to “and/or”. The terms“comprise”, “have”, and “include” are open-ended linking verbs. Anyforms or tenses of one or more of these verbs “comprises,” “comprising,”“has,” “having,” “includes,” and “including” are also open-ended. Forexample, any method that “comprises,” “has” or “includes” one or moresteps is not limited to possessing only those one or more steps and alsocovers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the description includes instances where the events occurs andinstances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In some embodiments, a therapeutic agent such as oralcolchicine is directed to the treatment and/or the amelioration of,reversal of, or stabilization of the symptoms of gout, familialMediterranean fever (FMF), pericarditis, Behçet's disease, atrialfibrillation, amyloidosis, calcium pyrophosphate deposition disease(pseudogout), cirrhosis of the liver, sarcoid arthritis, andinflammatory diseases described herein.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. Thus, as used herein, the term “administering”, when used inconjunction with an oral colchicine composition, can include, but is notlimited to, providing an oral colchicine composition into or onto thetarget tissue; providing an oral colchicine composition systemically toa patient by, e.g., oral administration whereby the therapeutic reachesthe target tissue or cells. “Administering” a composition may beaccomplished by injection, topical administration, and oraladministration or by other methods alone or in combination with otherknown techniques.

As used herein, the terms “patient,” “subject” and “individual” areintended to include living organisms in which certain conditions asdescribed herein can occur. Examples include humans, monkeys, cows,sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Ina preferred embodiment, the patient is a primate. In certainembodiments, the primate or subject is a human. In certain instances,the human is an adult. In certain instances, the human is child. Incertain instances, the human is elderly. In other instances, the humanis 65 years of age or older. Other examples of subjects includeexperimental animals such as mice, rats, dogs, cats, goats, sheep, pigs,and cows. By “pharmaceutically acceptable”, it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

Embodiments have been described where the techniques are implemented incircuitry and/or computer-executable instructions. It should beappreciated that some embodiments may be in the form of a method, ofwhich at least one example has been provided. The acts performed as partof the method may be ordered in any suitable way. Accordingly,embodiments may be constructed in which acts are performed in an orderdifferent than illustrated, which may include performing some actssimultaneously, even though shown as sequential acts in illustrativeembodiments.

Various aspects of the embodiments described above may be used alone, incombination, or in a variety of arrangements not specifically discussedin the embodiments described in the foregoing and is therefore notlimited in its application to the details and arrangement of componentsset forth in the foregoing description or illustrated in the drawings.For example, aspects described in one embodiment may be combined in anymanner with aspects described in other embodiments.

The present invention is further illustrated by the following Examples,which in no way should be construed as further limiting. The entirecontents of all of the references (including literature references,issued patents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated by reference.

EXAMPLES Example 1: Formulations

TABLE 2 Liquid Colchicine Formulation Ingredient % w/v Benzyl Alcohol0.3 Citric Acid, Anhydrous 0.2 Colchicine* 0.012 FD&C Red No. 40 0.01Dibasic Sodium Phosphate, Heptahydrate 1.2 Flavor Cherry 825.662 0.125Propylene Glycol 5 Glycerin 5 Sucralose 0.15 Xanthan Gum 0.15 Water Q.S.*Calculated on the anhydrous, solvent free basis

In some embodiments, the oral liquid formulation includes: the 0.3% w/vof benzyl alcohol, 0.2% w/v of anhydrous citric acids, 0.012% w/v ofcolchicine, 0.01% w/v of FD&C Red No. 40, 1.2% w/v or dibasic sodiumphosphate, heptahydrate, 0.125% w/v of flavor cherry 825.662, 5% w/v ofpropylene glycol, 0.15% w/v of sucralose, 0.15% w/v of xanthan gum, andwater as seen in Table 2.

Example 2: Stability

Colchicine has been shown to be unstable at room temperature insolution. An article published in Drug Development and IndustrialPharmacy, 15(11), 1905-1909 (1989) by Habib, et. al., investigated thestability of colchicine and showed that there is photodegradation ofcolchicine in solution, especially in the presence of glycerin, (up to a50% loss). The additives, such as lithium carbonate, p-aminobenzoicacid, and uric acid, used in this study to try and prevent thedegradation of the colchicine are not acceptable excipients for an oralsolution. Furthermore, these ingredients did not prevent the degradationof the colchicine. The stability studies described in this paper wereconducted over hours, which would not yield a pharmaceuticallyacceptable product.

Colchicine solutions are used in biological studies for cellular assays.Companies like BI (Biological Industries) sell a colchicine solution ina cellular buffering agent. The storage conditions are 2-8° in order toprevent degradation, as these types of solutions are not stable at roomtemperature. Furthermore, the safety information/MSDS for the buffersused to make these solutions state that it is harmful if ingested.

The product information from various suppliers of colchicine crystallinepowder for laboratory use state that colchicine should be stored atfreezing temperatures or refrigeration to maintain stability. CaymanChemical's product information regarding colchicine states that they donot recommend storing an aqueous solution made from their crystallinecolchicine powder for more than one day. Sigma product information oncolchicine says to store any made solutions between 2-8° for stabilitypurposes. Furthermore these product information sheets are for thecolchicine crystalline powder and any solutions described are not onlynot stable at room temperature for any period of time, but are notsolutions for oral consumption, as they are made with buffers andsolvents that are not for human consumption, such as DPBS, benzene, andchloroform. These solutions are for cellular assays in a laboratorysetting.

The colchicine injections for IV administration are made in single unitdoses, and the label and package inserts for these products specificallystate that the colchicine injections are for intravenous use only.

The colchicine compounded solutions for veterinary purposes are forimmediate use, and there is no stability data generated on these typesof products. As the prior art shows, colchicine solutions currentlymanufactured are not stable at room temperature for long term, andfurthermore none of the solutions described could be used for human oralconsumption.

Surprisingly, a stable oral colchicine solution that is even stable inthe presence of glycerin has been developed according to the invention.The colchicine solution is formulated and assayed for colchicine levels.Stability of the claimed formulation was tested at room temperature, 30°C., and 40° C. and assayed for the colchicine. Results can be found inTable 3 below. Table 4 shows further stability data up through 6 months.The fact that the oral solution was so stable after 6 months at anaccelerated temperature (40 degrees Celsius, which corresponds to 24months at room temperature) was quite surprising. Solutions ofcolchicine for oral administration to humans have not been developedbecause they were believed to be too unstable. The data presented hereinshow for the first time that an oral colchicine solution can remainstable with minimal degradants and thus have a long shelf lifeconsistent with commercial formulations.

TABLE 3 Stability Results of Colchicine Solution (% Label Claim) SampleResult API (colchicine drug substance)* 91.8% 3.5 months @ 5° 92.3% 3months @ 25° ± 2° C. 60% ± 5% RH(RT) 92.6% 3 months @ 30° ± 2° C. 65% ±5% RH(ICH) 91.3% 3 months @ 40° ± 2° C. 75% ± 5% RH(ACC) 91.1%*Calculated on the anhydrous, solvent-free basis

TABLE 4 Stability Report for Colchicine Solution, 0.12 mg/mL Test 6Conditions Initial 1 Month 2 Months 3 Months Months 25° C./60% RH 98.1%— 96.7% 97.3% 96.7% 30° C./65% RH 98.1% — 96.8% 96.5% 96.6% 40° C./75%RH 98.1% 96.6% 97.0% 96.7% 95.1%

These results show that there is no loss of colchicine from the initialraw API used and under all conditions after 6 months. These results showthat the colchicine solution of the invention is stable, even at hightemperatures. The colchicine does not degrade over time and underaccelerated conditions. The results were calculated on an as is basis.The colchicine solution in Table 4 was packaged in a 190 mL HDPE bottleand assayed by HPLC cUSP.

These results show the percent of label claim of colchicine in thesolution of the invention. The label claim of the liquid solution is0.12 mg/ml and the assay results of the active ingredient are reportedas percent of label claim. For instance, the label claim of an exemplarycolchicine solution of the invention is 0.12 mg/ml. The FDA requirementfor stability results for drugs is 90-110% label claim. These resultsshow that colchicine was not degraded over time under acceleratedconditions as well as at room temperature, which is surprising based onthe prior art.

The pH of the liquid solution was evaluated (Table 5). The results showthat the solution maintained a stable pH at accelerated conditions aswell at room temperature.

TABLE 5 Evaluation of pH of Colchicine Oral Solution (Initial pH = 6.6)Condition 1 month 2 months 3 months RT 6.48 6.61 6.59 30° 6.59 6.57 6.6040° 6.49 6.59 6.57

A desirable range of pH includes 6.2-7.2. In some embodiments the pHrange is 6.3-6.7.

Tables 6 and 7 below show data from USP antimicrobial preservativeseffectiveness tests. The product tested in both cases met therequirements of the Current USP for Oral Products (Category 3 Products).

TABLE 6 Initial Day 14 Day 28 Test Inoculum/ Log red Log red Organism mlCFU/ml (% red) CFU/ml (% red) S. aureus 6.1 × 10⁵ <10 >4 <10 >4 ATCC(>99.99) (>99.99) #6538 E. coli 5.8 × 10⁵ 1.98 × 10⁴ 1.47 1.46 × 10³2.60 ATCC (96.59) (>99.75) #8739 Ps. 8.6 × 10⁵ <10 >4 <10 >4 aeruginosa(>99.99) (>99.99) ATCC #9027 C. albicans 3.5 × 10⁵ 6.0 × 10³ 1.77 <10 >4ATCC (98.29) (>99.99) #10231 A. 3.5 × 10⁵ 1.1 × 10² 3.50 <10 >4brasiliensis (99.97) (>99.99) ATCC #16404

TABLE 7 Initial Day 14 Day 28 Inoculum/ Log red Log red Test Organism mlCFU/ml (% red) CFU/ml (% red) S. aureus 6.1 × 10⁵ 5.4 × 10³ 2.05 <10 >4ATCC #6538 (99.11) (>99.99) E. coli 5.8 × 10⁵ 6.5 × 10¹ 3.95 <10 >4 ATCC#8739 (99.99) (>99.99) Ps. aeruginosa 8.6 × 10⁵ <10 >4 <10 >4 ATCC #9027(>99.99) (>99.99) C. albicans 3.5 × 10⁵ 4.6 × 10² 2.88 <10 >4 ATCC#10231 (99.87) (>99.99) A. brasiliensis 3.5 × 10⁵ 1.1 × 10² 3.50 <10 >4ATCC #16404 (99.97) (>99.99)

Example 3: Colchicine Assay

This example presents the results of the evaluation of the applicationof the current USP Official (12/1/15-4/30/16) Monograph forColchicine/Colchicine Injection (Assay) for Colchicine Oral Liquid 0.12mg/mL. Evaluation included demonstration of system suitability,specificity for placebo and potentially interfering individual placebocomponents, and analysis of a sample preparation. The analysis wasperformed and documented within QCL project G8968.

Table 8, below, shows the sample materials that were used for theevaluation.

TABLE 8 Sample Materials Material Description Lot # Colchicine OralLiquid, 0.12 mg/mL Formula 0090A-1 011416B Colchicine Oral LiquidPlacebo Formula 0090A-1-PI 011416A Colchicine, USP API (Indena) 30670/HFD&C Red No. 40 47943 Flavor Cherry 825.662 FONA S1528930 Benzyl AlcoholSigma-Aldrich SHBD7983V

The current USP Assay method for Colchicine Injection refers to theAssay method described in the monograph for Colchicine drug substance.The method employs an isocratic reverse phase separation with stationaryphase L7 (C8) and UV detection at 254 nm with a 20 μL injection volume.The sample was prepared at a target concentration of 6 μg/mL Colchicineand compared to an external standard prepared at the same concentration.For the purposes of evaluation, Colchicine API was used for preparationof the external standard. Standard solutions were prepared in duplicateby the dilution of 12 mg Colchicine API to 200.0 mL in 50:50methanol:water diluent. 10.0 mL of the resulting stock standard wasfurther diluted to 100.0 mL in diluent to a concentration of 6 μg/mLColchicine working standard. For the preparation of the sample solution,8.0 mL (equivalent to 0.96 mg Colchicine) of the oral liquid was dilutedto 50.0 mL in diluent. 30.0 mL of the resulting solution was furtherdiluted to 100.0 mL in diluent to a concentration of 6 μg/mL Colchicineworking sample solution. The HPLC method parameters are summarized inTable 9 and example chromatography is provided in FIG. 1.

TABLE 9 HPLC Parameters Parameter Mobile Phase 45:55 0.5M monobasicpotassium phosphate:methanol, pH 5.5 Column Waters SPHERISORB ® 5 μm C84.6 × 250 mm Flow Rate 1.1 mL/min Column Temperature 21° C. InjectionVolume 20 μL Detection UV 254 nm

All specified system suitability parameters were met and maintainedthroughout the analysis. A summary of system suitability requirementsand results are provided in Table 10.

TABLE 10 System Suitability Parameters Parameter Requirement ResultColumn efficiency (Theoretical Plates) NLT 4500 7640 Retention Time -Colchicine 5.5-9.5 minutes 8.8 minutes RSD Colchicine Area NMT 2% 0.0%Standard Check Agreement 98.0-102.0% 99.6%

Colchicine Oral Liquid, 0.12 mg/mL, Formula 0090A-1, and the liquidplacebo includes ingredients at the concentrations shown in Table 5.Placebo and ingredients with the potential for UV absorptivity andchromatographic interference were examined (Table 11).

TABLE 11 Potential for Ingredient % % w/v Interference (Y/N) BenzylAlcohol 0.3 Y Citric Acid, Anhydrous 0.2 N Colchicine 0.012* — FD&C RedNo. 40 0.01 Y Dibasic Sodium Phosphate, Heptahydrate 1.2 N Flavor Cherry825.662 0.125 Y Glycerin USP (99.7%) 5.0 N Propylene Glycol 5.0 NSucralose 0.15 N Xanthan Gum 0.15 N Water Q.S. N *Calculated on theanhydrous, solvent free basis

The placebo formulation and individual ingredients benzyl alcohol, FD&CRed No. 40, and Flavor Cherry 825.662 were prepared at nominal (100% oftarget formulation) concentrations in diluent. An overlay of theresulting peaks including chromatograms of diluent blank and colchicinestandard are included in FIG. 2. Injections of benzyl alcohol and FD&CRed No. 40 resulted in single peaks that did not interfere at theretention time of colchicine. For the injection of Flavor Cherry825.662, a primary peak and four minor secondary peaks were recorded.The secondary flavor related peak, at a retention time of 8.9 minutes,elutes at the approximate retention time of Colchicine (8.8 minutes),contributing interference at approximately 1.5% of the area response ofa standard injection. Because the interfering peak completely co-eluteswith colchicine, the assay calculation was performed by subtraction ofthe flavor related peak response obtained from injection of the placebosolution from the colchicine response of the sample injections.

The sample preparation was injected in duplicate, with the calculationperformed against bracketing standard injections. The area response ofthe flavor related peak at retention time 8.9 minutes was subtractedfrom the area response of Colchicine in the sample injections. The assayresults obtained was 99.1% of the labeled amount.

The USP Colchicine Assay method evaluated as described in this report issuitable for the routine assay of Colchicine in Colchicine Oral Liquid,0.12 mg/mL. Minor interference due to the flavor cherry ingredient wasmitigated by concurrent injection of placebo sample with areasubtraction.

Example 4: Caco-2 Permeability of Colchicine

A Caco-2 study was conducted to compare the permeability of a colchicinesolution of the invention to commercially available tablet and capsules.This study is an in vitro test that uses a gut cell line to measurepermeability of the test articles. The results show that the colchicineoral solution has a similar permeability as the tablets and thecapsules. These results indicate that the bioavailability of thecolchicine solution in vivo will be similar to the tablets and thecapsules.

The purpose of this study was to determine the permeability ofColchicine from different formulations for the purpose of BCSclassification. This study was performed under non-GLP conditions. Allwork was performed with appropriate local health regulations and ethicalapproval. Colchicine monoisotopic mass is 399.17, and parent MW (freebase) is 399.44.

Procedure: Colchicine-Liquid—1 Bottle

Colchicine Liquid (1 mL equivalent to 300 μM Colchicine) was tested. Theprocedure included shaking the colchicine liquid bottle for a fewseconds before using. The solution was then diluted to the final assayconcentration.

Colchicine Tablets, USP+Sterile Water for Injection

Colchicine tablets, USP (equivalent to 0.6 mg or 300 μM colchicine) vialof 30 tablets were tested. 10 mL of sterile water was added forinjection.

First, the cover from the colchicine vial was removed. The contents of 2tablets were crushed into a fine powder. Then, 10 mL of sterile waterwas added, for injection, to the vial. The solution was then shaken welland sonicated for 10 minutes or until all of the powder was dissolved.Next, the solution was centrifuged for 10 minutes. The supernatant wasretained and was diluted to the final assay concentration.

Colchicine Capsules+Sterile Water for Injection

Colchicine capsules (equivalent to 0.6 mg or 300 μM colchicine), vial of100 capsules, were tested. 10 mL of sterile water was added forinjection.

First, the cover from Colchicine vial was removed. 2 capsules were thencarefully opened, and the contents were emptied into a vial. 10 mL ofsterile water was added for injection to the vial. The well was thenshaken and sonicated for 10 minutes or until all of the powder wasdissolved. The product was then centrifuged for 10 minutes. Thesupernatant was retained and was diluted to the final assayconcentration.

Methods Mass Spectrometry Method Development

The signal was optimized for each compound by ESI positive or negativeionization mode. An MS2 scan or an SIM scan was used to optimize thefragmenter voltage and a product ion analysis was used to identify thebest fragment for analysis, and the collision energy was optimized usinga product ion or MRM scan. An ionization ranking was assigned indicatingthe compound's ease of ionization.

Analysis

Samples were analyzed by LC/MS/MS using an Agilent 6410 massspectrometer coupled with an Agilent 1200 HPLC and a CTC PAL chilledautosampler, all controlled by MassHunter software (Agilent). Afterseparation on a C18 reverse phase HPLC column (Agilent Zorbax 3.5 um,2.1×30 mm) using an acetonitrile-water gradient, peaks were analyzed bymass spectrometry using ESI ionization in MRM mode; Solution A containedH₂O with 0.1% formic acid, and Solution B contained acetonitrile with0.1% formic acid. Tables 12 and 13 show data regarding HPLC gradient andexperimental conditions.

TABLE 12 HPLC Gradient Time Flow rate % A % B (min) (mL/min) MobilePhase Mobile Phase 0.37 1 98 2 1.88 1 5 95 2.06 1 5 95 2.14 1 98 2 3 198 2

TABLE 13 Caco-2 Permeability: Experimental Conditions Test TestTransport Reference Analytical Article conc. pH Direction compoundsmethod Colchicine - 10 μM 5.7/7.4 A→B ranitidine LC/MS/MS LiquidColchicine, 6.5/7.4 B→A talinolol USP - Tablets Colchicine - 7.4/7.4metoprolol Capsules

Summary of Procedure:

Caco-2 cells were grown in tissue culture flasks and were trypsinized,suspended in medium, and the suspensions were applied to wells of aMillipore 96 well Caco-2 plate. The cells were allowed to grow anddifferentiate for three weeks, and fed at 2-day intervals.

For Apical to Basolateral (A→B) permeability, the test agent was addedto the apical (A) side and amount of permeation was determined on thebasolateral (B) side; for Basolateral to Apical (B→A) permeability, thetest agent was added to the B side and the amount of permeation wasdetermined on the A side. The A-side buffer contained 100 μM Luciferyellow dye, in Transport Buffer (1.98 g/L glucose in 10 mM HEPES, lxHank's Balanced Salt Solution) at pH 5.7, 6.5, or 7.4, and the B-sidebuffer used was Transport Buffer, pH 7.4. Caco-2 cells were incubatedwith these buffers for 2 hours, and the receiver side buffer was removedfor analysis by LC-MS/MS.

To verify the Caco-2 cell monolayers were properly formed, aliquots ofthe cell buffers were analyzed by fluorescence to determine thetransport of the impermeable dye Lucifer Yellow. Any deviations fromcontrol values were reported.

Data expressed as permeability (P _(app)): P _(app) =dQ/Dt/C ₀ A.

dQ/dt: rate of permeation; C₀: initial concentration of test agent; A:area of monolayer. For bidirectional permeability studies, Efflux Ratio(RE): R_(e)=P_(app)(B→A)/P_(app)(A→B). Table 14 shows mass spectrometrymethod development. Tables 15 and 16 show data regarding Caco-2permeability data displaying a data summary and individual data fromreplicates, respectively.

Results

TABLE 14 Mass Spectrometry Method Development: MS/MS Test ESI ArticleMonoisotopic Polar- Precursor Product Ionization (API) Mass ization m/2zm/z classification Colchicine 399.17 Positive 399.9 358.2 1 Ionizationclassification: 1 = Highly ionizable; 2 = Intermediately ionizable; 3 =Poorly ionizable m/z: Mass-to-Charge (or, mass-to-double charge) ratioof analyte

TABLE 15 Caco-2 Permeability: Data Summary mean mean A → B B → A PappPapp Test Test pH (10-6 (10-6 Efflux Article conc. (A/B) cm s-1) cm s-1)ratio Comment ranitidine 10 μM 6.5/7.4 0.27   2.1  7.8 Class III BCStalinolol 10 μM 6.5/7.4 0.073  6.6 90.4 P-gp efflux control metoprolol10 μM 6.5/7.4 13.7   27.2  2.0 high BCS control (Class I BCS)Colchicine- 10 μM 5.7/7.4 0.10   5.4 54.0 Liquid Colchicine, 10 μM5.7/7.4 0.12   4.9 40.8 USP- Tablets Colchicine- 10 μM 5.7/7.4 0.15  5.2 34.7 Capsules Colchicine- 10 μM 6.5/7.4 0.16   5.4 33.8 LiquidColchicine, 10 μM 6.5/7.4 0.17   5.2 30.6 USP- Tablets Colchicine- 10 μM6.5/7.4 0.14   5.3 37.9 Capsules Colchicine- 10 μM 7.4/7.4 0.12   5.848.3 Liquid Colchicine, 10 μM 7.4/7.4 0.13   5.8 44.6 USP-TabletColchicine- 10 μM 7.4/7.4 0.18   6.4 35.6 Capsules

TABLE 16 Caco-2 Permeability: Individual Data from Replicates Trans-Papp A → B port (10⁻⁶ cm s-1) Post- Test pH Direc- 1^(st) 2^(nd) 3^(rd)Assay Article (A/B) tion replicate replicate replicate Mean RecoveryCol- 5.7/ A → B  0.10  0.10  0.10  0.10 61% chicine- 7.4 B → A 5.2 5.25.4 5.1 Liquid 6.5/ A → B  0.19  0.13  0.16  0.16 63% 7.4 B → A 5.6 5.15.5 5.4 7.4/ A → B  0.13  0.13  0.091  0.12 64% 7.4 B → A 5.3 6.1 6.15.7 Col- 5.7/ A → B  0.15  0.11  0.091  0.12 65% chicine, 7.4 B → A 4.75.1 5.0 4.9 USP- 6.5/ A → B  0.12  0.13  0.25  0.17 63% Tablets 7.4 B →A 4.7 5.4 5.6 5.1 7.4/ A → B  0.16  0.15  0.093  0.13 63% 7.4 B → A 5.55.7 6.3 5.6 Col- 5.7/ A → B  0.15  0.17  0.13  0.15 63% chicine- 7.4 B →A 5.0 5.1 5.4 5.0 Capsules 6.5/ A → B  0.18  0.084  0.15  0.14 64% 7.4 B→ A 5.2 5.1 5.5 5.1 7.4/ A → B  0.16  0.19  0.19  0.18 63% 7.4 B → A 6.36.2 6.6 6.2 P_(app): apparent permeability rate coefficient

QC Criteria

All wells utilized in this study passed QC criteria for epithelialmonolayer integrity. All wells utilized exhibited Lucifer Yellowtransport less than 2% (unless noted otherwise). All wells that wereutilized in this assay exhibited TEER (Trans-Epithelial ElectricalResistance) readings greater than 1500 Ohms, also in accordance with QCcriteria for acceptable monolayer integrity. FIG. 3 shows thecalibration curve of colchicine in Caco-2 transport buffer.

BCS criterion classifies all 3 batches of Colchicine tested in thisstudy as exhibiting low permeability across the pH ranges tested (5.7,6.5, and 7.4). All 3 batches of Colchicine tested in this study (USPtablets, capsules, and liquid) exhibited a very similar permeabilityprofile (i.e. low permeability with high efflux ratios and similarpost-assay recovery levels).

The apparent permeability rate coefficients (P_(app)) for all 3 batchesof Colchicine tested in this study (in the absorptive, A→B, transportdirection) approximates only 1% (or less) of the Papp coefficient of theBCS high permeability control compound, metoprolol.

This value of 1% does not meet the 90% threshold of FDA criteria for BCSclassification as high permeability. As a result, all 3 batches ofColchicine tested in this study are classified as exhibiting lowpermeability for BCS purposes. (Current EMA guidelines for BCSclassification are 80% of the positive control for high permeability).FIG. 4 shows a colchicine chromatograms in Caco-2 buffer. Table 17 showsthe MRM transition for colchicine. Table 18 shows cumulative colchicineoral solution data at 25° C.±2° C./60%±5% RH, which has been stable forat least 3 months. Table 19 shows the cumulative colchicine oralsolution data at 40° C.±2° C./75%±5% RH, which has been stable for atleast 3 months. It is mandatory to add a suitable preservative tonon-sterile solutions, it maintain microbiological integrity for theremainder of the shelf-life. The preservative should also be stable tomaintain its anti-microbial activity. Benzyl alcohol, a preservative inthe colchicine oral solution tested in Tables 18 and 19, is stable andis compatible with colchicine as well as all excipients.

The data presented herein also shows that over a period of time theactive drug-substance (colchicine) does not degrade more than theaccepted limit and the each of the degradants does not exceed a certainthreshold. No such information is available in the literature for liquidcolchicine. As you can see, the data herein show that, fortunately, thedegradants, after 3-month storage, even at 40° C./75% RH (indicative ofstability to 24-month at room temperature), are either not detected ornot quantifiable (very small quantity).

A liquid formulation of colchicine has been made for oral consumptionwhich is stable, has a compatible and stable preservative, and underdegrades minimally in longer-term storage conditions (well below theacceptable limit).

TABLE 17 MRM Transition for Colchicine: MS/MS Method Development Mono-Test Isotopic ESI Precursor Product Ionization Article Mass Polarizationm/z m/z Classification Colchicine 399.17 Positive 399.9 358.2 1 m/z:mass-to-charge ratio of analyte Ionization Classification: 1 = HighlyIonizable

TABLE 18 Cumulative Colchicine Oral Solution Data at 25° C. ± 2° C./60%± 5% RH Stability Data: Colchicine Oral Solution Batch No.: PD16033Storage Condition: 25° ± 2° C./60% ± 5% RH Drug Substance Batch No.:31626/H Container Closure: 190-cc, Oblong, HDPE Bottles with 38-400 mmAuto-Loc CRC with a foil liner Test Parameter Acceptance Results[Storage (Months)] Analytical Procedure Criteria 0 1 2 3 6 Description Aslightly Conforms Conforms Conforms Conforms Organoleptic hazy, redliquid with a cherry odor. pH 6.0 to 7.2 6.6 6.6 6.6 6.6 USP <791>Density 1.00 to 1.04  1.02  1.02  1.02  1.02 USP <841> g/mL at 25° C.Colchicine Assay 0.108 to 99.3  100.0  100.0  99.8  In-house HPLC 0.132mg/mL (90.0 to 110.0% of label claim) Benzyl Alcohol Assay 2.4 to 99  99   98   98   In-house HPLC 3.6 mg/mL (80 to 120% of label claim)Related Substances In-house HPLC β-lumicolchicine NMT 1.0% NT NT NT NDγ-lumicolchicine NMT 1.0% NT NT NT ND Colchiceine NMT 1.0% NT NT NT <LOQAny other NMT 1.0% NT NT NT ND individual unknown impurities TotalImpurities NMT 5.0% NT NT NT <LOQ HPLC: High Performance LiquidChromatography NMT: Not More Than NLT: Not Less Than NT: Not Tested(Testing not required by development specification.)

TABLE 19 Cumulative Colchicine Oral Solution Data at 40° C. ± 2° C./75%± 5% RH Stability Data: Colchicine Oral Solution Batch No: PD16033Storage Condition: 40° ± 2° C./75% ± 5% RH Drug Substance Batch No.:31626/H Container CLosure: 190-cc, Oblong, HDPE Bottles with 38-400 mmAuto-Loc CRC with a foil liner Test Parameter Acceptance Results[Storage (Months)] Analytical Procedure Criteria 0 1 2 3 6 Description Aslightly hazy, Conforms Conforms Conforms Conforms Organoleptic redliquid with a cherry odor. pH 6.0 to 7.2 6.6 6.6 6.6 6.6 USP <791>Density 1.00 to 1.04  1.02  1.02  1.02  1.02 USP <841> g/mL at 25° C.Colchicine Assay 0.108 to 99.3  99.2  99.6  97.4  In-house HPLC 0.132mg/mL (90.0 to 110.0% of label claim) Benzyl Alcohol Assay 2.4 to 99  97   96   93   In-house HPLC 3.6 mg/mL (80 to 120% of label claim)Related Substances In-house HPLC β-lumicolchicine NMT 1.0% NT NT NT NDγ-lumicolchicine NMT 1.0% NT NT NT ND Colchiceine NMT 1.0% NT NT NT <LOQAny other NMT 1.0% NT NT NT ND individual unknown impurities TotalImpurities NMT 5.0% NT NT NT <LOQ HPLC: High Performance LiquidChromatography NMT: Not More Than NLT: Not Less Than NT: Not Tested(Testing not required by development specification.)

REFERENCES

-   Habib, M. J. et al (2008). “Influence of certain additives on the    photostability of colchicine solutions.” Drug Development and    Industrial Pharm. 15(11):1905-1909.-   Stewart, B. H. et al. (1995). “Comparison of Intestinal    Permeabilities Determined in Multiple In Vitro and In Situ Models:    Relationship to Absorption in Humans.” Pharm. Res. 12:693-699.-   Artursson, P. et al. (2001). “Caco-2 Monolayers in Experimental and    Theoretical Predictions of Drug Transport.” Adv. Drug Deliv. Rev.    46:27-43.-   Yee, Shiyin (1997). “In Vitro Permeability across Caco-2 Cells    (Colonic) Can Predict In Vivo (Small Intestinal) Absorption in    Man—Fact or Myth.” Pharm. Res 14(6):763-766.-   Yu, L. X. et al (2002). “Biopharmaceutics Classification System: The    Scientific Basis for Biowaiver Extensions.” Pharm Res. 19(7):    921-925.

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the appended claims. The advantages and objects of theinvention are not necessarily encompassed by each embodiment of theinvention.

1. A method of treating a colchicine sensitive disorder, comprisingorally administering a composition, comprising a liquid colchicineformulation to a human subject having a colchicine sensitive disorder inan effective amount to treat the disorder.
 2. The method of claim 1,wherein the colchicine sensitive disorder is selected from gout,prophylactic treatment of gout, familial Mediterranean fever (FMF),prophylactic treatment of FMF, pericarditis, prophylactic treatment ofpericarditis, Behçet's disease, atrial fibrillation, prophylactictreatment of atrial fibrillation, amyloidosis, calcium pyrophosphatedeposition disease (pseudogout), cirrhosis of the liver, sarcoidarthritis, inflammatory diseases, and disk diseases and related spinaldisorders.
 3. A liquid solution or suspension suitable for oraladministration comprising colchicine and a pharmaceutically acceptablesolvent system comprised of one or more agents selected from the groupconsisting of water, glycols, buffering agents, sweeteners, flavoringagents, preservatives, and dyes.
 4. The liquid solution or suspension ofclaim 3, wherein the pharmaceutically acceptable solvent systemcomprises about 0.1-0.3% (w/v) citric acid (anhydrous).
 5. The liquidsolution or suspension of claim 3, wherein the pharmaceuticallyacceptable solvent system comprises about 1.2% (w/v) dibasic sodiumphosphate, heptahydrate.
 6. The liquid solution or suspension of claim3, wherein the pharmaceutically acceptable solvent system comprisesabout 5% (w/v) glycerin USP (99.7%).
 7. The liquid solution orsuspension of claim 3, wherein the pharmaceutically acceptable solventsystem comprises about 5% (w/v) propylene glycol.
 8. The liquid solutionor suspension of claim 3, wherein the preservative is about 0.1-0.3%(w/v) citric acid, anhydrous.
 9. The liquid solution or suspension ofclaim 3, wherein the preservative is about 0.3% (w/v) of benzyl alcohol.10. The liquid solution or suspension of claim 3, wherein the thickeningagent comprises about 0.1-0.2% (w/v) xanthan gum.
 11. The liquidsolution or suspension of claim 3, wherein the concentration ofcolchicine in the solution is 0.01-1.0 mg/mL.
 12. The liquid solution orsuspension of claim 3, wherein colchicine comprises about 0.01-0.015%(w/v).
 13. The liquid solution or suspension of claim 3, wherein thepharmaceutically acceptable solvent system is comprised of one or moreagents selected from the group consisting of water, propylene glycol,glycerin, benzyl alcohol, dibasic sodium phosphate, heptahydrate, citricacid, xanthan gum, sucralose, a dye, and a flavoring agent and/or tasteenhancing agent.
 14. The liquid solution or suspension of claim 3,wherein the pharmaceutically acceptable solvent system is comprised ofthe following components: Ingredient % w/v Benzyl Alcohol 0.3 CitricAcid, Anhydrous 0.2 Colchicine 0.012* FD&C Red No. 40 0.01 DibasicSodium Phosphate, Heptahydrate 1.2 Flavor Cherry 825.662 0.125 PropyleneGlycol 5 Glycerin 5 Sucralose 0.15 Xanthan Gum 0.15 Water Q.S.*Calculated on the anhydrous, solvent free basis


15. An oral liquid colchicine solution or suspension that is stable for30 days to 24 months at ambient and refrigerated temperature conditions.16. The liquid colchicine solution or suspension of claim 15, whereinthe solution is stable for 3 months to 12 months at acceleratedconditions.
 17. The liquid colchicine solution or suspension of claim15, wherein the solution has a stable pH.
 18. The liquid colchicinesolution or suspension of claim 15, wherein the solution has a viscosityin the range of 40-800 cps.
 19. The liquid colchicine solution orsuspension of claim 15, wherein the solution is volume packaged 60mL-473 mL.
 20. The liquid colchicine solution or suspension of claim 17,wherein the pH is range is 6.2-7.2.